Effector T Cell Reprogramming to Central Memory Phenotype
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Solution Overview
Problem
Existing adoptive T cell therapy methods face challenges in generating central memory T cells with high proliferative ability, as most infused T cells are well-differentiated effector or effector memory cells with limited persistence and self-renewal capacity.
Innovation Solution
A method involving the use of histone deacetylase inhibitors (HDACi) and interleukin-21 (IL-21) to reprogram effector T cells into central memory T cells, enhancing their persistence and proliferative ability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If well-differentiated effector T cells are used for adoptive T cell therapy, then immediate antitumor activity is achieved, but persistence and self-renewal capacity are limited
Solution Approach 1:
The patent applies parameter changes by treating effector T cells with histone deacetylase inhibitors (HDACi) to alter epigenetic parameters. This treatment modifies chromatin structure and gene expression patterns, effectively resetting the differentiation state of T cells. The HDACi treatment enables well-differentiated effector T cells to be reprogrammed into a central memory-like phenotype, thereby improving persistence and self-renewal capacity while maintaining antitumor activity.
2Duration of action of moving object
If central memory T cells are generated from effector T cells, then self-renewal capacity is improved, but the process requires additional culturing steps
Solution Approach 1:
The patent employs preliminary action by performing HDACi treatment during the initial expansion phase of T cell culture. Rather than requiring separate differentiation steps after T cell generation, the epigenetic modification is integrated into the early culturing process. This preliminary intervention establishes a central memory-like phenotype that persists throughout subsequent therapy, simplifying the overall workflow while achieving the desired persistence improvement.
3Reliability
If histone deacetylase inhibitor and IL-21 are used to reprogram T cells, then central memory phenotype is achieved, but culture conditions become more complex
Solution Approach 1:
The patent merges multiple functions into a unified culture system by combining HDACi treatment with IL-21 supplementation in the same culture medium. This integration allows simultaneous achievement of epigenetic reprogramming and cytokine-driven differentiation toward a central memory phenotype. The combined approach consolidates what could be separate sequential steps into a single coordinated culture condition, reducing overall process complexity while maintaining the reliability of central memory T cell generation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method effectively generates a population of lymphocytes enriched for central memory T cells, which are more persistent and have increased proliferative capacity, potentially improving the efficacy of adoptive T cell therapy.
Implementation Method 1
culturing the starting population of lymphocytes comprising T EFF cells or the sample enriched in T EFF cells in the presence of a histone deacetylase inhibitor (HDACi)
Implementation Method 2
interleukin-21 (IL-21), each in an amount sufficient to re-program the T EFF cells into T CM cells
Data Source
Figure 1A~1B
Figure 1C
Figure 2A
AI summary
The present disclosure provides methods for re-programming effector T cells to a central memory phenotype comprising culturing the effector T cells with a histone deacetylase inhibitor (HDACi) and IL-21. Further provided are methods of treating cancer comprising administering the central memory T cells.